Hemophilia A is a congenital bleeding disorder caused by genetic mutations affecting a plasma protein, termed factor VIII (fVIII), whose function is to facilitate blood clotting. State of the art treatment of hemophilia A consists of frequent intravenous infusion of fVIII containing products. The current limitations to treating hemophilia are 1) access to fVIII products, 2) the cost of fVIII products, 3) the development of immune responses against fVIII that block treatment efficacy and 4) morbidity due to joint disease resulting from repeated bleeding into individual joints. Due to the limited amount of fVIII needed to provide clinical benefit to the patient, hemophilia A is an attractive disease for cell and gene-based therapy. This is evidenced by the fact that there have been three phase I clinical trials for gene therapy of hemophilia A conducted. In addition, it has been demonstrated that liver transplantation from a non-hemophilia A individual into a hemophilia A patient cures the disease. However due to organ shortage and transplant associated risks, treatment of hemophilia by orthotopic liver transplantation is not practical. Several investigators now have demonstrated that bone marrow-derived cells have the ability to repopulate liver tissue and express liver-specific proteins. Therefore, bone marrow-derived stem cells potentially could serve as a safe and effective therapeutic for hemophilia A. We, propose to evaluate the potential for bone marrow-derived stem cells as a treatment option for hemophilia A and identify the donor cell lineages that synthesize fVIII using a murine model of hemophilia A. The results obtained from the proposed studies should 1) aid in defining the relative roles different liver cell types play in fVIII biosynthesis and 2) facilitate the design of novel cellular and gene transfer-based therapies for hemophilia A. [unreadable] [unreadable] [unreadable]